Impaired vascular vasomotor function plays an essential role in the pathogenesis and prognosis of cardiovascular disease. The endothelium is central to the regulation of vascular tone through the synthesis and release of opposing vasoactive substances, particularly nitric oxide (NO) and endothelin-1 (ET-1). It has been suggested that a disruption in the balance between the opposing effects of these vasoactive substances, favoring constriction, contributes to the age-related decline in vasomotor regulation. To date, however, the vast majority of studies (in humans) have focused on age-associated changes in NO bioavailability, there is currently very little information regarding the effects of aging on ET-1 vasoconstrictor activity and its potential impact on vasomotor function. This represents a critical void in our understanding of the regulation of vascular tone with human aging. Moreover, increased ET-1-dependent vasoconstriction has been linked to the etiology of a number of age-related pathologies including hypertension, vasospasm, heart failure and coronary artery disease. The specific aims of the present proposal will be to determine if : 1) endogenous ET-1 vasoconstrictor activity increases with age in healthy adult humans and, if so, whether the increase is progressive with age from young adulthood and are mediated by both ET-1 receptor subtypes; 2) the vascular vasoconstrictor response to ET-1 is altered with age; 3) increased ET-1 vasoconstrictor activity contributes to the age-related impairment in endothelial vasodilator function observed in healthy, sedentary adult humans; and 4) a program of regular aerobic exercise reduces ET-1-mediated vasoconstriction in previously sedentary middle-aged and older adults. To address these aims, forearm vascular responses to selective and nonselective ET-1 receptor antagonists as well as exogenous ET-1 will be determined in healthy adult humans (20-79 yr). In addition, the vasodilator response to acetylcholine and sodium nitroprusside will be determined in the absence and presence of ET-1 receptor blockade. ET-1 vasoconstrictor activity will also be assessed before and after a 12-week aerobic exercise training program. The proposed study should provide new and clinically useful information regarding the influence of age on the activity of the ET-1 system and its impact on vasomotor regulation as well as the potential benefical effects of exercise in reducing ET-1 vasoconstrictor tone.